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Objectives: To investigate associations of the carriage of single nucleotide polymorphisms (SNPs) of proteins involved in the immune response of patients with brucellosis., Methods: A case control study of patients with brucellosis upon WHO criteria. Blood genomic analysis was performed by RFLP- PCR for the detection of SNPs: i) at promoters -376 G > A (rs1800750); -308 G > A (rs 1,800,629); -238 G > A (rs361525) of the TNF gene, ii) at -896 A > G Asp299Gly (rs4986790) and -1196 C > T Thr399Ile (rs4986791) positions of the TLR-4 gene. Logistic regression analysis of factors related to brucellar spondylodiscitis was performed., Results: Patients with brucellosis (n = 105) were male (n = 67, 63.8 %); mean age (SD): 49.51(18.31); spondylodiscitis (n = 30), sacral osteomyelitis (n = 21). Carriage of the minor frequency A alleles at -238 of the promoter region of TNF was greater in patients than in controls (11.4% vs 2.6 %, p < 0.001). In a stepwise regression model including host variables and TNF-238 G A -1 genotype, only the last one was associated with brucellar spondylodiscitis [OR 2.91 (CI95 % 1.02-8.31), p = 0.047]., Conclusions: In our cohort, the association of one TNF SNP of patients with brucellosis, in particular spondylodiscitis, might be prognostic whereas further investigation of the exact role in the host immune response is required., Competing Interests: Declaration of competing interest E. J. Giamarellos-Bourboulis has received honoraria from Abbott Products Operations, bioMérieux, France, Brahms GmbH, GSK, Sobi AB and Xbiotech Inc; independent educational grants from Abbott Products Operations, bioMérieux Inc, Johnson & Johnson, MSD, UCB, Swedish Orphan Biovitrum AB; and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grants EPICCROWN-2, POINT and Homi-Lung (granted to the Hellenic Institute for the Study of Sepsis). G. Dalekos is an advisor or lecturer for Pfizer, Roche, Sanofi and Sobi, and received research grants from Gilead and has served as PI in studies for Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals., (Copyright © 2024. Published by Elsevier B.V.)

24 Z -Masticadienonic acid (MNA) and 24 Z -isomasticadienonic acid (IMNA) are the major triterpenic acids in Chios Mastic Gum (CMG), a resin derived from Pistacia lentiscus var. Chia . Despite their promising pharmacological potential, limited information is available due to the complexity of isolating them in pure form. This study developed a chemo-selective method for isolating MNA and IMNA and investigated their chemical transformation through isomerization of the external double bond and A-ring contraction of the triterpene scaffold. A rapid method for isolating MNA from CMG was first established, followed by a high-yield acid-catalyzed procedure to obtain both 24 Z and 24 E isomers of IMNA. Additionally, a basic catalyzed isomerization of IMNA led to the formation of two new compounds with A-ring contraction, which could serve as novel scaffolds for the design of new triterpene analogs. The mixture of MNA/IMNA, along with the individual compounds and their semi-synthetic analogs, exhibited significant anti-inflammatory activity. Notably, 24 E -isomasticadienonic acid and 24 Z -2-hydroxy-3-oxotirucalla-1,8,24-trien-26-oic acid, a previously unreported compound, significantly reduced the mRNA expression levels of Tnf , Il6 , and Nfkb1 in RAW 264.7 macrophage cells.

Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn's disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). The study analysed articles published in JCR journals from 2019 to 2024. The search strategy comprised the MESH, free terms of "Neuroinflammation", and selective searches for the following single biomarkers that had previously been selected from the relevant literature: "High mobility group box 1/HMGB1", "Toll-Like-Receptor 4/TLR-4", "Interleukin-1/IL-1", "Interleukin-6/IL-6", "Transforming growth factor beta/TGF-β", and "Tumour necrosis factor-alpha/TNF-α". These queries were all combined with the MESH terms "Epileptogenesis" and "Epilepsy". We found 243 articles related to epileptogenesis and neuroinflammation, with 356 articles from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 55 evaluated by the authors. A total of 21 articles were included in the qualitative evaluation, including 18 case-control studies, 2 case series, and 1 prospective study. As conclusion, this systematic review provides acceptable support for five biomarkers, including TNF-α and some of its soluble receptors (sTNFr2), HMGB1, TLR-4, CCL2 and IL-33. Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control of epileptic seizures. Their value will be better defined by future studies.

Community-acquired pneumonia (CAP) is a common respiratory disease in children. This prospective cohort study of 110 children with CAP and 100 healthy children investigated the relationship between the levels of vitamin A, D and E and inflammatory markers, such as tumour necrosis factor (TNF-a), interleukin-1 (IL-1), interleukin-10 (IL-10), neutrophils (NE) and C-reactive protein (CRP), in CAP. The haemoglobin, leukocyte concentration, NE, monocytes and CRP concentration in the CAP group showed significant differences ( P < 0.05). The levels of vitamin A, D and E in the CAP group were lower than those in the control group, while the levels of TNF-a and IL-1 were higher than in the control group; the differences were statistically significant ( P < 0.05). The IL-10 levels showed no significant differences ( P > 0.05). Pearson analysis revealed that the vitamin A, D and E levels were all correlated with the TNF-a, IL-10 and CRP levels ( P < 0.05). The vitamin A, D and E levels of the CAP children were lower than those of the healthy children. Thus, the content of fat-soluble vitamins is correlated with the secretion of TNF-a and IL-10. The research provides a new direction for the prevention, diagnosis and treatment of CAP., Competing Interests: Conflict of interest: The authors declare that they have no competing interests., (© 2024 the author(s), published by De Gruyter.)

Objective: To detect the continuous blood purification (CBP)'s application value in patients with urosepsis caused by ureteral calculi and heart failure after catheterization., Methods: This is a clinical comparative study. Sixty patients with ureteral calculi complicated with heart failure and urosepsis were admitted at Affiliated Hospital of Hebei University from January 2021 to March 2023 randomly split into control and experimental group(n=30). Based on conventional treatment after indwelling the DJ tube, the experimental group was treated with CBP therapy. The control group dealt with conventional anti-inflammatory, oxygen inhalation and other treatments only. Compared and analyzed in terms of alterations in blood inflammatory factors, cardiac function, BNP prior to and after therapy, blood pressure, blood WBC recovery time, and so on., Results: TNF-a, CRP, and PCT levels in the control and experimental groups were substantially more prominent than the average reference value prior to treatment. They decreased considerably at distinct time points after therapy, with substantial distinctions (p< 0.05). A more meaningful decrease was noticed in the experimental group in comparison with the control group (p< 0.05). BNP and cardiac function were improved in both groups prior to and after therapy, and the amelioration of indexes in the experimental group was more substantial than that in the control group after therapy, with statistically considerable distinctions. The improvement time in experimental group was earlier than in the control group, with statistically substantial differences., Conclusion: Patients with urosepsis complicated with heart failure after indwelling DJ tube have their inflammatory factors improved significantly, with more thorough excretion by using conventional treatment combined with CBP therapy., Competing Interests: Conflicts of interest: None., (Copyright: © Pakistan Journal of Medical Sciences.)

Adequate diet, physical activity, and dietary supplementation with muscle-targeted food for special medical purposes (FSMP) or dietary supplement (DS) are currently considered fundamental pillars in sarcopenia treatment. The aim of this study is to evaluate the effectiveness of a DS (containing hydroxy-methyl-butyrate, carnosine, and magnesium, for its action on muscle function and protein synthesis and butyrate and lactoferrin for their contribution to the regulation of gut permeability and antioxidant/anti-inflammation activity) on muscle mass (assessed by dual X-ray absorptiometry (DXA)), muscle function (by handgrip test, chair test, short physical performance battery (SPPB) test, and walking speed test), inflammation (tumor necrosis factor-alpha (TNF-a), C-reactive protein (CRP), and visceral adipose tissue (VAT)) and gut axis (by zonulin). A total of 59 participants (age 79.7 ± 4.8 years, body mass index 20.99 ± 2.12 kg/m 2 ) were enrolled and randomly assigned to intervention ( n = 30) or placebo ( n = 28). The skeletal muscle index (SMI) significantly improved in the supplemented group compared to the placebo one, +1.02 (CI 95%: -0.77; 1.26), p = 0.001; a significant reduction in VAT was observed in the intervention group, -70.91 g (-13.13; -4.70), p = 0.036. Regarding muscle function, all the tests significantly improved ( p = 0.001) in the supplemented group compared to the placebo one. CRP, zonulin, and TNF-alpha significantly decreased ( p = 0.001) in intervention, compared to placebo, -0.74 mg/dL (CI 95%: -1.30; -0.18), -0.30 ng/mL (CI 95%: -0.37; -0.23), -6.45 pg/mL (CI 95%: -8.71; -4.18), respectively. This DS improves muscle mass and function, and the gut muscle has emerged as a new intervention target for sarcopenia.

Objective: Endoplasmic reticulum stress (ERS) and Toll-like receptor 2 (TLR2) signaling play an important role in inflammatory bowel disease (IBD); however, the link between TLR2 and ERS in IBD is unclear. This study investigated whether Thapsigargin (TG) -induced ER protein expression levels contributed to TLR2-mediated inflammatory response., Methods: The THP-1 cells were treated with TLR2 agonist (Pam3CSK4), ERS inducer Thapsigargin (TG) or inhibitor (TUDCA). The mRNA expressions of TLR1-TLR10 were detected by qPCR. The production and secretion of inflammatory factors were detected by PCR and ELISA. Immunohistochemistry was used to detect the expressions of GRP78 and TLR2 in the intestinal mucosa of patients with Crohn's disease (CD). The IBD mouse model was established by TNBS in the modeling group. ERS inhibitor (TUDCA) was used in the treatment group., Results: The expression of TLRs was detected via polymerase chain reaction (PCR) in THP-1 cells treated by ERS agonist Thapsigargin (TG). According to the findings, TG could promote TLR2 and TLR5 expression. Subsequently, in TLR2 agonist Pam3CSK4 induced THP-1 cells, TG could lead to increased expression of the inflammatory factors such as TNF-α, IL-1β and IL-8, and ERS inhibitor (TUDCA) could block this effect. However, Pam3CSK4 did not significantly impact the GRP78 and CHOP expression. Based upon the immunohistochemical results, TLR2 and GRP78 expression were significantly increased in the intestinal mucosa of patients with Crohn's disease (CD). For in vivo experiments, TUDCA displayed the ability to inhibit intestinal mucosal inflammation and reduce GRP78 and TLR2 proteins., Conclusions: ERS and TLR2 is upregulated in inflammatory bowel disease, ERS may promote TLR2 pathway-mediated inflammatory response. Moreover, ERS and TLR2 signaling could be novel therapeutic targets for IBD.

Background: Methamphetamine is a substance that causes neurotoxicity and its use is increasing in recent years. Literature highlights cognitive impairment resulting from Methamphetamine use. The aim of the present study is to evaluate the relationship between cognitive impairment and inflammatory processes in adolescents with Methamphetamine use disorder., Methods: The study included 69 adolescents aged 15-19 years, comprising 37 participants with Methamphetamine Use Disorder and 32 healthy controls. Central Nervous System Vital Signs was used to detect cognitive impairment. Childhood Trauma Questionnaire-33 and The Children's Depression Inventory scales were used. In addition, venous blood was collected from the volunteers. Biochemical parameters (IL-1beta, IL-6, TNF-a, BDNF, FAM19A5, TAS, TOS) were analyzed., Results: Our study showed that (I) IL-6 and TNF-a levels of Methamphetamine users were lower than the healthy group; (II) BDNF levels of Methamphetamine users were higher than the healthy group; (III) mean Neurocognitive Index in cognitive tests of Methamphetamine using adolescents was negatively correlated with duration of Methamphetamine use and BDNF levels., Conclusions: Our study suggests that Methamphetamine use may have a negative effect on cognitive functions.

Background & Objective: Besides the clinical and laboratory research on the COVID-19 virus, the bioinformatics study in the field of genetics of immunity to COVID-19 is of particular importance. In this account, studies show that in patients with COVID-19, the level of tumor necrosis alpha (TNFα) and interleukin-6 (IL-6) is high and in severe cases of COVID-19, the production of IL-6, TNF-α, and other cytokines increases profoundly. On the other hand, investigating the molecular structure and receptors of IL-6 and TNFα and the structural analysis of the receptor proteins may potentially help to develop new therapeutic plans for COVID-19 infection., Methods: To identify genes with significant and different expressions in patients with COVID-19 in a microarray data set containing transcriptional profiles from GEO as a functional genomic database the GEO query package version 2.64.2 in a programming language R version 4.2.1 was downloaded. In this way, functional enrichment analysis for DEGs, WikiPathways, REGO, gene ontology, and STRING database was also investigated and employed., Results: The structure and function of pro-inflammatory cytokines TNFα and IL-6 involved in the pathogenesis of COVID-19 were investigated, and in general, after performing various analyses in this study and extracting A series of genes with different expressions from the KEGG database, the final 5 DEGs include CXCL14, CXCL6, CCL8, CXCR1, TNFRSF10, and the relationship and expression effects of them were observed in different pathways., Conclusion: IL-6 and TNFα were involved in immunological processes that had a direct and indirect relationship with the activation of cytokines, including IL6 and TNF-a, and cytokine storm, and this indicates their role in the formation of problems and complications, including ARDS, in COVID-19 patients. Of course, determining the effectiveness of each of these genes requires more specialized and clinical studies., Competing Interests: There is no conflict of interest., (© 2024.)

Objective: This study aimed to evaluate the prognostic significance of serum inflammatory factor levels in patients with acute ischemic stroke undergoing revascularization therapy., Methods: The study included 94 patients with acute ischemic stroke who underwent revascularization therapy at our hospital. The primary outcome was the modified Rankin scale (mRS) score assessed three months post-treatment. Patients were categorized into two groups: those with a poor prognosis (mRS score > 2) and those with a good prognosis (mRS score≤2). The patients were divided into two groups based on the type of revascularization treatment received: thrombus extraction or intravenous thrombolysis. Logistic regression analysis was used to identify independent risk factors associated with the prognosis of patients treated with recanalization for acute ischemic stroke., Results: Among the 94 patients, 59 had a good prognosis, and 35 had a poor prognosis. At admission, the patients in the good prognosis group exhibited lower NIHSS scores, shorter hospital stays, fewer previous cardiac events, lower LDL levels, fasting glucose, IL-6, and TNF-a compared to those in the poor prognosis group (all P < 0.05). Logistic regression analysis identified TNF-a (odd ratio (OD), 1.623; 95% confidence interval (CI), 1.282-1.933; P = 0.035) and IL-6 (OD, 1.055; 95% CI, 1.024-1.088, P = 0.023) as independent risk factors for poor prognosis in patients after revascularization. Additionally, pre-hospital NIHSS scores, IL-6, and TNF-a levels were significantly lower in the good prognosis group compared to the poor prognosis group, with these differences being statistically significant., Conclusion: IL-6 and TNF-α may serve as prognostic markers for outcomes following revascularization therapy in patients with acute ischemic stroke, including those receiving intravenous thrombolysis.

Due to substantial homology between the human and zebrafish genome and a high level of conservation of the innate immune system across species, zebrafish larvae have become an invaluable research tool for studying inflammation and modelling inflammatory disease. However, further microscopy techniques need to be developed for better profiling of inflammation and in particular, integrated cytokine responses to different stimuli - approaches are currently largely limited to assessment of changes in cytokine gene transcription and in vivo visualisation using transgenics, which is limited in terms of the number of cytokines that may be assessed at once. In this study, after confirming substantial homology of human vs zebrafish cytokine amino acid sequences, immunofluorescence staining using antibodies directed at human cytokines was performed. Inflammatory cytokine signalling responses to experimental tailfin transection was assessed over 24 h (1 hpi (hours post injury), 2 hpi, 4 hpi, 24 hpi) in zebrafish larvae, with experimental end point at 120 h post fertilization (hpf). When immunofluorescence results were compared to responses observed in rodent and human literature, it is clear that the cytokines follow a similar response, albeit with a condensed total time course. Notably, tumor necrosis factor-α and monocyte chemoattractant protein-1 increased and remained elevated over the 24-h period. In contrast, interleukin-1β and interleukin-6 peaked at 4 hpi and 2 hpi respectively but had both returned to baseline levels by 24 hpi. Macrophage migration inhibitory factor was lowest at 1 hpi, potentially encouraging macrophage movement into the site of injury, followed by a sharp increase. This protocol provides valuable insight into inflammation over a time course and more so, provides an affordable and accessible method to comprehensively assess inflammation in zebrafish disease models., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tracey Ollewagen reports financial support was provided by National Research Fund South Africa., (© 2023 The Authors.)

Introduction: Cytokines and chemokines play an important role in shaping innate and adaptive immunity in response to infection and vaccination. Systems serology identified immunological parameters predictive of beneficial response to the BNT162b2 mRNA vaccine in COVID-19 infection-naïve volunteers, COVID-19 convalescent patients and transplant patients with hematological malignancies. Here, we examined the dynamics of the serum cytokine/chemokine responses after the 3 rd BNT162b2 mRNA vaccination in a cohort of COVID-19 infection-naïve volunteers., Methods: We measured serum cytokine and chemokine responses after the 3 rd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in COVID-19 infection-naïve individuals by a chemiluminescent assay and ELISA. Anti-Spike binding antibodies were measured by ELISA. Anti-Spike neutralizing antibodies were measured by a pseudotype assay., Results: Comparison to responses found after the 1 st and 2 nd vaccinations showed persistence of the coordinated responses of several cytokine/chemokines including the previously identified rapid and transient IL-15, IFN-γ, CXCL10/IP-10, TNF-α, IL-6 signature. In contrast to the transient (24hrs) effect of the IL-15 signature, an inflammatory/anti-inflammatory cytokine signature (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CXCL8/IL-8, IL-1Ra) remained at higher levels up to one month after the 2 nd and 3 rd booster vaccinations, indicative of a state of longer-lasting innate immune change. We also identified a systemic transient increase of CXCL13 only after the 3 rd vaccination, supporting stronger germinal center activity and the higher anti-Spike antibody responses. Changes of the IL-15 signature, and the inflammatory/anti-inflammatory cytokine profile correlated with neutralizing antibody levels also after the 3 rd vaccination supporting their role as immune biomarkers for effective development of vaccine-induced humoral responses., Conclusion: These data revealed that repeated SARS-Cov-2 BNT162b2 mRNA vaccination induces both rapid transient as well as longer-lasting systemic serum cytokine changes associated with innate and adaptive immune responses., Clinical Trial Registration: Clinicaltrials.gov, identifier NCT04743388., Competing Interests: Author ET has received honoraria from Astra/Zeneca and Pfizer. Authors PH and SK were employed by the company Leidos Biomedical Research, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Rosati, Terpos, Homan, Bergamaschi, Karaliota, Ntanasis-Stathopoulos, Devasundaram, Bear, Burns, Bagratuni, Trougakos, Dimopoulos, Pavlakis and Felber.)

Aging leads to a decline in stem cell activity by reducing the repopulation rate and paracrine potential, ultimately diminishing efficacy in vivo. TNF-α can exert inflammatory and cell death actions via Erk by binding to TNFR-1, and survival and tissue repair actions via Akt by binding to TNFR-2. Aged cells are reported to have insufficient expression of TNFR-2, indicating that aged adipose-derived stem cells (ADSCs-E) lack the ability for cell survival and immune control compared to young ADSCs (ADSCs-Y). This study aims to assess the preconditioning effect of SP on the response of ADSCs-E to inflammation. ADSCs-E were treated with SP and then exposed to a high dose of TNF-α for 24 h. Consequently, ADSC-E exhibited weaker viability and lower TNFR2 levels compared to ADSC-Y. In response to TNF-α, the difference in TNFR2 expression became more pronounced in ADSC-E and ADSC-Y. Moreover, ADSC-E showed a severe deficiency in proliferation and paracrine activity. However, preconditioning with SP significantly enhanced the viability of ADSCs-E and also restored TNFR2 expression and paracrine potential, similar to ADSC-Y under inflammatory conditions. Our findings support the idea that preconditioning with SP has the potential to restore the cellular function of senescent stem cells before transplantation.

Omega-3 fatty acids are potential anti-inflammatory agents that may exert beneficial outcomes in diseases characterised by increased inflammatory profile. The purpose of this study was to comprehensively evaluate the existing research on the effectiveness of n-3 fatty acid supplementation in lowering levels of circulating inflammatory cytokines in patients with heart failure (HF). From the beginning until October 2022, randomised controlled trials (RCTs) were the subject of PubMed, Scopus, Web of Science, and Cochrane Library literature search. Omega-3 fatty acid supplementation vs. placebo were compared in eligible RCTs to see how they affected patients with HF in terms of inflammation, primarily of tumour necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and c-reactive protein (CRP). A meta-analysis employing the random effects inverse-variance model and standardised mean differences was performed to assess group differences. Ten studies were included in this systematic review and meta-analysis. Our main analysis (k = 5) revealed a beneficial response of n-3 fatty acid supplementation on serum TNF-a (SMD: - 1.13, 95% CI: - 1.75- - 0.50, I 2  = 81%, P = 0.0004) and IL-6 levels (k = 4; SMD: - 1.27, 95% CI: - 1.88- - 0.66, I 2  = 81%, P < 0.0001) compared to placebo; however, no changes were observed in relation to CRP (k = 6; SMD: - 0.14, 95% CI: - 0.35-0.07, I 2  = 0%, P = 0.20). Omega-3 fatty acid supplementation may be a useful strategy for reducing inflammation in patients with HF, but given the paucity of current studies, future studies may increase the reliability of these findings., (© 2023. The Author(s).)

Background: To investigate the expression levels of blood biomarkers interleukin-6 (IL-6), tumour necrosis factor (TNF-a), and intestinal fatty acid binding protein (iFABP) in patients with post-stroke depression (PSD), and their correlation with PSD occurrence., Methods: Clinical data of stroke patients admitted to the First People's Hospital of Wenling from December 2017 to December 2022 were retrospectively analyzed. Patients were classified into two groups based on their Hamilton Depression Rating Scale (HAMD) scores: PSD and nonPSD groups. The blood levels of IL-6, TNF-a, and iFABP were compared between the two groups, and their association with PSD occurrence was analyzed., Results: The PSD group had significantly higher levels of IL-6, TNF-a, and iFABP. The combined detection of these biomarkers demonstrated a greater predictive value for PSD occurrence compared to the individual detection of each biomarker., Conclusions: The study indicates that the levels of IL-6, TNF-a, and iFABP in the blood are significantly increased in patients with PSD. The combined detection of these biomarkers can effectively predict the occurrence of PSD, indicating high clinical value., Competing Interests: All the authors declare that they have no conflict of interest in this work.Conflict of Interest: The authors stated that they have no conflicts of interest regarding the publication of this article., (2023 Linlin Wang, Chen Chunyou, Jingang Zhu, Xianjun Bao, Xiaoxiao Tao, published by CEON/CEES.)

Memory B cells are comprised of unswitched (CD27+IgD+) and switched (CD27+IgD-) subsets. The origin and function of unswitched human memory B cells are debated in the literature, whereas switched memory B cells are primed to respond to recurrent infection. Unswitched memory B cells have been described to be reduced in frequency with severe SARS-CoV2 infection and here we characterize their activation status, BCR functionality, and contribution to virally-induced cytokine production. Analyses of whole blood from healthy individuals, people immunized against SARS-CoV2, and those who have had mild and severe SARS-CoV2 infection, confirm a reduction in the frequency of unswitched memory B cells during severe SARS-CoV2 infection and demonstrate this reduction is associated with increased levels of systemic TNFα. We further document how severe viral infection is associated with an increased frequency of 'IgD+' only memory B cells that correlate with increased IgG autoantibody levels. Unswitched and switched memory B cells from severe SARS-CoV2 infection displayed evidence of heightened activation with a concomitant reduction in the expression of the inhibitory receptor CD72. Functionally, both populations of memory B cells from severe SARS-COV2 infection harbored a signaling-competent BCR that displayed enhanced BCR signaling activity in the unswitched population. Finally, we demonstrate that B cells from mild SARS-CoV2 infection are poised to secrete pro-inflammatory cytokines IL-6 and TNFα. Importantly, unswitched memory B cells were a major producer of IL-6 and switched memory B cells were a major producer of TNFα in response to viral TLR ligands. Together these data indicate that B cells contribute to the inflammatory milieu during viral infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Castleman, Santos, Lesteberg, Maloney, Janssen, Mould, Beckham, Pelanda and Torres.)

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune cytokine that belongs to the TNF superfamily of receptor ligands. The cytokine exists as either a transmembrane or a soluble molecule, and targets two distinct receptors, TNF-α receptor 1 (TNFR1) and TNF-α receptor 2 (TNFR2), which activate different signaling cascades and downstream genes. TNF-α cellular responses depend on its molecular form, targeted receptor, and concentration levels. TNF-α plays a multifaceted role in normal physiology that is highly relevant to human health and disease. In the central nervous system (CNS), this cytokine regulates homeostatic functions, such as neurogenesis, myelination, blood-brain barrier permeability and synaptic plasticity. However, it can also potentiate neuronal excitotoxicity and CNS inflammation. The pleiotropism of TNF-α and its various roles in the CNS, whether homeostatic or deleterious, only emphasizes the functional complexity of this cytokine. Anti-TNF-α therapy has demonstrated effectiveness in treating various autoimmune inflammatory diseases and has emerged as a significant treatment option for CNS autoimmune diseases. Nevertheless, it is crucial to recognize that the effects of this therapeutic target are diverse and complex. Contrary to initial expectations, anti-TNF-α therapy has been found to have detrimental effects in multiple sclerosis. This article focuses on describing the various roles, both physiological and pathological, of TNF-α in the CNS. Additionally, it discusses the specific disease processes that are dependent or regulated by TNF-α and the rationale of its use as a therapeutic target., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gonzalez Caldito.)

Aim of the Study: Akt is involved in upregulating the insulin-signaling pathways essential for maintaining glucose metabolism. Glycosphingolipids are involved in the pathogenesis of glucose intolerance and associated target organ injury. On the other hand, oral administration of b-glucosylceramide (GC) has been shown to alleviate insulin resistance. The present study aimed to determine the effects of oral administration of insulin and GC, separately and in combination, on Akt expression and the subsequent effect on metabolic syndrome characteristics in leptin-deficient mice., Material and Methods: Four groups of leptin-deficient ob/ob mice were orally administered for four weeks: vehicle, GC, short-acting insulin, and GC combined with insulin. Mice were followed for hepatic Akt expression and changes in tumor necrosis factor a (TNF-a) level, hyperlipidemia, and liver damage., Results: In mice that received insulin or GC, particularly those that received both, the liver phosphorylation of Akt was significantly increased compared to those that received only vehicle. Serum TNF-a levels decreased in insulin-treated mice. These effects were associated with alleviating glucose intolerance and hyperlipidemia, as manifested by a significant glucose tolerance test improvement and reductions in serum triglyceride and cholesterol levels. Significant liver damage alleviation was noted by liver enzyme reductions in all treated groups, along with liver steatosis in the insulin-treated mice., Conclusions: These data established the potential use of oral insulin administration with glycosphingolipids to alleviate glucose intolerance and associated liver damage and hyperlipidemia via increased Akt expression in the liver. The data support targeting Akt as a potent therapeutic target for metabolic syndrome., Competing Interests: Y. Ilan is a consultant for Teva; ENZO; Protalix; Betalin Therapeutics; Immuron; SciM; Natural Shield; Oberon Sciences; Tiziana Pharma; Plantylight; Exalenz Bioscience. The authors declare no conflict of interest., (Copyright © 2023 Clinical and Experimental Hepatology.)

Background: Type 2 diabetes mellitus (T2DM) is a low-grade, chronic inflammatory disease, associated with increased cardiovascular risk. The purpose of this systematic review/ meta-analysis was to evaluate the effects of aerobic exercise training (AET) on inflammatory markers in T2DM patients., Methods: The literature search was conducted utilizing PubMed, Web of Science, Embase, and the Cochrane Library from their inception up to April 2022. We screened only for randomized controlled trials (RCTs) investigating the effects of AET on C-reactive protein (CRP) and adipokines: adiponectin, resistin, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-a), along with changes in anthropometric indices and glycemic control in adult T2DM patients. Pooled post-exercise weighted mean differences (WMDs) with 95% Confidence Intervals (CIs) were calculated for all outcomes of interest between exercise-treated patients and controls., Results: Twenty-six RCTs involving 1239 T2DM patients were retrieved from the databases for meta-analysis. The cumulative results showed that post-AET inflammatory markers were lower in exercise-treated patients compared to controls regarding CRP (mg/L): WMD: -0.91; 95%CIs: -1.43, -0.40; p < 0.001 resistin (mg/ml): (WMD: -2.08; 95%CIs: -3.32, -0.84; p < 0.001); TNF-a (pg/ml): (WMD: -2.70; 95%CIs: -4.26, -1.14; p < 0.001), and IL-6 (pg/ml): (WMD: -1.05; 95%CIs: -1.68, -0.43; p < 0.001). Those effects were accompanied by significant amelioration of fasting glucose (mg/dl) (WMD: -13.02; 95%CIs: -25.39, -0.66; p = 0.04), HbA1c (%) (WMD: -0.51; 95%CIs: -0.73, -0.28, p < 0.001), and fat mass (%) (WMD: -3.14; 95%CI: -4.71, -1.58; p < 0.001). Our meta-analysis demonstrated less-consistent results for adiponectin (μg/ml), (WMD: 1.00; 95%CI: -0.12, 2.12; p = 0.08) and body-mass index (kg/m 2 ) (WMD: -1.34; 95%CI: -2.76, 0.08; p = 0.06) tending to differ between AET and control group., Conclusions: AET can significantly reduce the inflammatory burden in T2DM patients. by ameliorating the circulating levels of CRP, resistin, TNF-a and IL-6, even without accompanied significant weight-loss. The clinical impact of those anti-inflammatory effects of AET needs to be determined., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Helicobacter pylori colonizes the gastric mucosa and induces chronic inflammation., Methods: Using a mouse model of H. pylori -induced gastritis, we evaluated the mRNA and protein expression levels of proinflammatory and proangiogenic factors, as well as the histopathological changes in gastric mucosa in response to infection. Five- to six-week-old female C57BL/6N mice were challenged with H. pylori SS1 strain. Animals were euthanized after 5-, 10-, 20-, 30-, 40- and 50-weeks post infection. mRNA and protein expression of Angpt1, Angpt2, VegfA, Tnf-α, bacterial colonization, inflammatory response and gastric lesions were evaluated., Results: A robust bacterial colonization was observed in 30 to 50 weeks-infected mice, which was accompanied by immune cell infiltration in the gastric mucosa. Compared to non-infected animals, H. pylori- colonized animals showed an upregulation in the expression of Tnf-A , Angpt2 and VegfA at the mRNA and protein levels. In contrast, Angpt1 mRNA and protein expression was downregulated in H. pylori -colonized mice., Conclusion: Our data show that H. pylori infection induces the expression of Angpt2, Tnf-A and Vegf-A in murine gastric epithelium. This may contribute to the pathogenesis of H. pylori -associated gastritis, however the significance of this should be further addressed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Malespín-Bendaña, Alpízar-Alpízar, Figueroa-Protti, Reyes, Molina-Castro, Une and Ramírez-Mayorga.)

Background: Understanding immune responses after HBV vaccination is important to prevent HBV infection in PLWH and to achieve successful treatment., Methods: Thirty-two PLWHs with CD4 + cell count > 350 cells/µL and HIV RNA < 200 copies/mL were vaccinated with 20 µg of HBV vaccine at weeks 0, 4, and 24 in this prospective study. We measured total HIV DNA levels, HBsAb titers and HBsAg-specific T-cell responses during follow-up time., Results: All patients achieved protective HBsAb titer after immunization. The magnitude of the IFN-r and TNF-a response to HBsAg was 22.0 (IQR: 6.5-65.0) and 106.50 (IQR: 58.5-203.0) spot-forming cells (SFC)/10 5 PBMC, respectively at week 0. The level of IFN-r secreted at weeks 12 and weeks 36 to 48 was comparable with that at week 0. However, IFN-r response was higher at weeks 12 than that at weeks 36 to 48 ( p = 0.02). The level of TNF-a secreted at weeks 12 was higher than that at week 0 ( p < 0.001). Total HIV DNA levels were 2.76 (IQR: 2.47-3.07), 2.77 (IQR: 2.50-3.09), 2.77 (IQR: 2.41-2.89) log 10 copies/10 6 PBMCs at weeks 0, 12, 36 to 48, respectively. No correlation was observed between IFN-r and TNF-a levels and HBsAb titer as well as total HIV DNA levels after immunization., Conclusion: Humoral immunity was satisfactory, but cellular immunity and decline in HIV reservoir were not optimal after HBV vaccine immunization in these patients.

Introduction: Among the cancers that impacts men, prostate cancer considerably raises deaths for males around the world. Persons with tumours can have a localized or advanced form of the illness., Objective: The present study aimed to determining the relationship between the level of cytokines (IL-10 and TNF-a) and PSA in the sera of patients and compared it with healthy., Materials and Methods: A case control study consist of three group included was in this study. The first group involves 50 patients with PC were observation in Al-Amal Oncology Hospital in the period from April 2021 to April 2022 under the supervision of oncology specialists was included in this study. Second group consist of 30 patients. They have benign hyper plaisa (BHP), this group has been collected from urosergical department . Third group was include 20 healthy volunteers (non prostate cancer and non BHP). Prostate specific antigen (PSA) was measured by mini - VIDAS device using kit supplied by Biomerieux - France. IL-10 and TNF-a levels were measured by ELISA technique using kit supplied by CAUSABIO - China., Results: Results of the present study showed the 60-69 years age group scored highest percentage in benign (56.7%), malignant (54.0%), compared to control (healthy) (50.0%), while > 69 years scored least percentage in these groups (3.3%, 14.0%, and 25.0%) respectively with significant different (p< 0.05). Additionally, the IL-10 and PSA scored highest mean levels in the malignant group (1.22 ± 0.23 and 27.66 ± 6.31), while TNF-a scored highest mean levels in a benign group (0.30 ± 0.11). The least mean level of IL-10 was in healthy (0.42 ± 0.15), TNF-a in malignant (0.23 ± 0.03), and PSA in benign (6.73 ± 1.36). Finally, there is a significant difference among age groups and PSA, IL-10, and TNF-parameters., Conclusions: We concluded the PSA, TNF-a and IL-10 parameters are play important roles in pathogenesis patients with prostate cancer. PCa is high prevalence in elderly population.

Background: Autoimmune hepatitis (AIH) is an inflammatory liver disease that is characterized histologically by interface hepatitis, biochemically by elevated transaminase levels, and serologically by the presence of autoantibodies. Toll-like receptor (TLR)-4 is a TLR family member that, upon activation in hepatocytes, initiates a cascade of events. Interleukin-2 (IL-2) and tumour necrosis factor α (TNF-α) are potent inflammatory cytokines secreted in AIH, playing an important role in the early development of inflammation and hepatocyte damage., Objectives: This study examined the role of cyclosporine in AIH and illustrated its actions on altered hepatic function in the silica-induced AIH model., Methods: AIH was induced in Wistar rats using sodium silicate. The rats were divided into four groups: the control group, silica-AIH group, cyclosporine-treated group, and prevention group. TLR-4 and IL-2 mRNA expressions in liver tissues were tested by RTPCR., Results: AIH was associated with up-regulation of liver enzymes, IL-2 and TLR-4 gene expression, while cyclosporine significantly down-regulated the expression of both. The relative quantity of TLR-4 mRNA was 1±0, 13.57±1.91, 4±0.38, and 2±0 in control, AIH, cyclosporine, and prevention groups, respectively (p<0.001). Also, the relative quantity of IL-2 mRNA was 1±0, 14.79±1.42, 7.07±0.96, and 3.4±0.55 in control, AIH, cyclosporine, and prevention groups, respectively (p<0.001). Additionally, immunohistochemical staining for TNF-α in liver sections was increased in the silica-AIH group but was found to decrease in the cyclosporine-treated and prevention groups., Conclusion: This study advocates the therapeutic role of cyclosporine in treating immune-mediated hepatic diseases. Cyclosporine improves histological alterations in the liver and inhibits the production of proinflammatory cytokines., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

One of the major mediators of neuroinflammation in PD is tumour necrosis factor alpha (TNF-α), which, similar to other cytokines, is produced by activated microglia and astrocytes. Although TNF-α can be neuroprotective in the brain, long-term neuroinflammation and TNF release can be harmful, having a neurotoxic role that leads to death of oligodendrocytes, astrocytes, and neurons and, therefore, is associated with neurodegeneration. Apart from cytokines, a wide family of molecules with homologous structures, namely chemokines, play a key role in neuro-inflammation by drawing cytotoxic T-lymphocytes and activating microglia. The objective of the current study was to examine the levels of the serum TNF-α and CCL2 (Chemokine (C-C motif) ligand 2), also known as MCP-1 (Monocyte Chemoattractant Protein-1), in PD patients compared with healthy controls. We also investigated the associations between the serum levels of these two inflammatory mediators and a number of clinical symptoms, in particular, disease severity and cognition. Such an assessment may point to their prognostic value and provide some treatment hints. PD patients with advanced stage on the Hoehn-Yahr scale showed an increase in TNF-α levels compared with PD patients with stages 1 and 2 ( p = 0.01). Additionally, the UPDRS score was significantly associated with TNF-α levels. CCL2 levels, however, showed no significant associations.

Background: Honey has been shown to possess anti-inflammatory and bactericidal properties that may be useful for the prevention and treatment of infections as well as of acute and chronic inflammatory diseases. The antimicrobial potency of honey could be attributed to its physicochemical characteristics combined with the presence of certain compounds, such as hydrogen peroxide and polyphenols. Honey's bacteriostatic or bactericidal capacity varies depending on its composition and the bacterial type of each infection. Nevertheless, not all honey samples possess anti-inflammatory or antibacterial properties and their mechanism of action has not been clearly elucidated. Objectives: We therefore investigated the anti-inflammatory properties of three different honey samples that derived from different geographical areas of Greece and different botanical origins, namely, arbutus, chestnut, and fir; they were compared to manuka honey, previously known for its anti-inflammatory and antibacterial activity. Materials and Methods: To test the anti-inflammatory activity of the different samples, we utilized the in vivo model of LPS-driven inflammation, which induces septic shock without the presence of pathogens. To evaluate the antibacterial action of the same honey preparations, we utilized the cecal-slurry-induced peritonitis model in mice. Since acute inflammation and sepsis reduce the biotransformation capacity of the liver, the expression of key enzymes in the process was also measured. Results: The administration of all Greek honey samples to LPS-stimulated mice revealed a potent anti-inflammatory activity by suppressing the TNFα serum levels and the expression of TNFα and iNOS in the liver at levels comparable to those of the manuka honey, but they had no effect on IL-6 or IL-1β. It was shown that the LPS-induced suppression of CYP1A1 in the liver was reversed by Epirus and Crete fir honey, while, correspondingly, the suppression of CYP2B10 in the liver was reversed by Evros chestnut and Epirus fir honey. The effect of the same honey samples in polymicrobial peritonitis in mice was also evaluated. Even though no effect was observed on the disease severity or peritoneal bacterial load, the bacterial load in the liver was reduced in mice treated with Evros chestnut, Epiros fir, and Crete fir, while the bacterial load in the lungs was reduced in Epirus arbutus, Crete fir, and manuka honey-treated mice. Conclusion: Our findings suggest that these specific Greek honey samples possess distinct anti-inflammatory and antibacterial properties, as evidenced by the reduced production of pro-inflammatory mediators and the impaired translocation of bacteria to tissues in septic mice. Their mode of action was comparable or more potent to those of manuka honey.

Background: Previous studies have explored associations between Tumour Necrosis factor-Alpha ( TNF-a ) polymorphisms and Schizophrenia. Their results were controversial. We conducted a meta-analysis to clarify the association between TNF-a  - 308 G/A(rs1800629), -1031T/C(rs1799964), -863C/A(rs1800630) and -857 C/T (rs1799724) polymorphisms and Schizophrenia., Methods: All the studies that investigated the association between TNF-a polymorphisms and Schizophrenia published before 15 October 2020 were included in. The literature were comprehensively searched and identified in 2 English databases and 2 Chinese databases. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated., Results: For -1031 T/C polymorphism, at the overall analysis, significantly decreased Schizophrenia risk was found in T allele in the allele model ( p  = 0.006, OR = 0.88) and increased Schizophrenia risk was found in TC + CC genotype in the dominant model ( p  = 0.005, OR = 1.17). Similarly, the same results were obtained when pooled analyses were included in high-quality studies (allele model: p  = 0.005, OR = 0.86; dominant model: p  = 0.007, OR = 1.20). In addition, when stratified by ethnicity, the results showed that in allele model, the T allele decreased Schizophrenia risk in East Asian ( p  = 0.031, OR = 0.90)., Conclusion: The association may most likely result from less-credible, rather than from true associations or biological factors on the TNF-a - 1031 T/C polymorphism with Schizophrenia risk.KeypointsFor -1031T/C polymorphism, at the overall analysis, significantly decreased schizophrenia risk was found in T allele in the allele model, and increased schizophrenia risk was found in TC + CC genotype in the dominant model.In allele model, the T allele decreased schizophrenia risk in East Asian when stratified by ethnicity, and in the dominant model, TC + CC genotype increased schizophrenia risk in East Asian.

Objective: Dyslipidemia is one of the major public health problems in China. It is characterized by multisystem dysregulation and inflammation, and oxidant/antioxidant balance has been suggested as an important factor for its initiation and progression. The objective of this study was to determine the relationship between prevalence of dyslipidemia and measured changes in the levels of proinflammatory cytokines (IL-6, TNF-a, and MCP-1), thiobarbituric acid-reactant substances (TBARS), and serum total antioxidant capacity (TAC) in serum samples., Study Design: A cross-sectional survey with a purposive sampling of 2,631 enrolled participants (age 18-85 years) was performed using the adult population of long-term residents of the municipality of east coast China in Fujian province between the years 2017 and 2019. Information on general health status, dyslipidemia prevalence, and selected mediators of inflammation was collected through a two-stage probability sampling design according to socioeconomic level, sex, and age., Methods: The lipid profile was conducted by measuring the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) with an autoanalyzer. Dyslipidemia was defined according to National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria, and patients with it were identified by means of a computerized database. Serum parameters including IL-6/TNF-a/MCP-1, TBARS, and TAC were measured in three consecutive years. Familial history, education level, risk factors, etc. were determined. The association between dyslipidemia and serum parameters was explored using multivariable logistic regression models. Sociodemographic, age, and risk factors were also investigated among all participants., Results: The mean prevalence of various dyslipidemia in the population at baseline (2017) was as follows: dyslipidemias, 28.50%; hypercholesterolemia, 26.33%; high LDL-C, 26.10%; low HDL-C, 24.44%; and hypertriglyceridemia, 27.77%. A significant effect of aging was found among all male and female participants. The mean levels of serum Il-6/TNF-a/MCP-1 were significantly higher in all the types of dyslipidemia among male participants. Female participants with all types of dyslipidemia but low HDL-C showed an elevation of IL-6 and MCP-1 levels, and those with dyslipidemias and hypercholesterolemia presented higher levels of TNF-a compared to the normal participants. The oxidative stress marker TBARS increased among all types of dyslipidemia except hypertriglyceridemia. All participants with different types of dyslipidemia had a lower total antioxidant capacity. Correlation analysis showed that cytokines and TBARS were positively associated with age, obesity, and diabetes mellitus, but not sex, sedentary leisure lifestyle, hypertension, and CVD/CHD history. The activity of TAC was negatively associated with the above parameters., Conclusions: The correlation between the prevalence of dyslipidemia and the modification of inflammation status was statistically significant. The levels of proinflammatory cytokines, oxidative stress, and antioxidant capacity in serum may reflect the severity of the lipid abnormalities. These promising results further warrant a thorough medical screening in enhanced anti-inflammatory and reduced oxidative stress to better diagnose and comprehensively treat dyslipidemia at an early stage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hong, Lin, Ye, Yang, Huang, Duan and Xie.)

The pathophysiology of pain in patients suffering from rotator cuff (RC) tendinopathy or tears has been examined in various ways. Several molecules from tissue samples taken from the subacromial bursa, supraspinatus tendon, glenohumeral joint fluid, and synovium as well as from peripheral blood have been investigated. This article explores these studies, the assessed biomarkers, and groups their results according to the status of tendon integrity (tendinopathy or tear). Through a structured PubMed database search, 9 out of 658 articles were reviewed. Interleukins, mostly IL-1b and its antagonist, IL-1ra, matrix Metalloproteinases (MMPs), the vascular endothelial growth factor (VEGF) and TNF-a are biomarkers directly searched for correlation to pain level. Most studies agree that IL-1b is directly positively correlated to the degree of pain in patients with RC tendinopathy, especially when the examined sample is taken from the subacromial bursa. VEGF, and TNF-a have been related to shoulder pain preoperatively and TNF-a has also been linked with sleep disturbance. Further studies pointing to more biomarkers taken from the subacromial bursa or tendon directly relating to pain degree are warranted.

There are limited studies on neuroprotection from repeated subconcussive head impacts (RSHI) following docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) supplementation in contact sports athletes. We performed a randomized, placebo-controlled, double-blinded, parallel-group design trial to determine the impact of 26 weeks of DHA+EPA supplementation (n = 12) vs. placebo (high-oleic safflower oil) (n = 17) on serum concentrations of neurofilament light (NfL), a biomarker of axonal injury, and inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)) in National Collegiate Athletic Association Division I American football athletes. DHA+EPA supplementation increased (p < 0.01) plasma DHA and EPA concentrations throughout the treatment period. NfL concentrations increased from baseline to week 26 in both groups (treatment (<0.001); placebo (p < 0.05)), with starting players (vs. non-starters) showing significant higher circulating concentrations at week 26 (p < 0.01). Fish oil (DHA+EPA) supplementation did not mitigate the adverse effects of RSHI, as measured by NfL levels; however, participants with the highest plasma DHA+EPA concentrations tended to have lower NfL levels. DHA+EPA supplementation had no effects on inflammatory cytokine levels at any of the timepoints tested. These findings emphasize the need for effective strategies to protect American football participants from the effects of RSHI.

Tumor necrosis factor (TNF)-like cytokine 1A (TL1A), a member of the TNF family, exists in the form of membrane-bound (mTL1A) and soluble protein (sTL1A). TL1A binding its only known functional receptor death domain receptor 3 (DR3) affects the transmission of various signals. This study first proposed that the TL1A/DR3 axis was significantly upregulated in patients and mice with both asthma and high TNF-a expression and in TNF-a-stimulated epithelial Beas-2B cells. Two independent approaches were used to demonstrate that the TL1A/DR3 axis of mice was strongly correlated with TNF-a in terms of exacerbating asthmatic epithelial-mesenchymal transformation (EMT). First, high expression levels of EMT proteins (e.g., collagen I, fibronectin, N-cadherin, and vimentin) and TL1A/DR3 axis were observed when mice airways were stimulated by recombinant mouse TNF-a protein. Moreover, EMT protein and TL1A/DR3 axis expression synchronously decreased after mice with OVA-induced asthma were treated with infliximab by neutralizing TNF-a activity. Furthermore, the OVA-induced EMT of asthmatic mice was remarkably improved upon the deletion of the TL1A/DR3 axis by knocking out the TL1A gene. TL1A siRNA remarkably intervened EMT formation induced by TNF-a in the Beas-2B cells. In addition, EMT was induced by the addition of high concentrations of recombinant human sTL1A with the cell medium. The TL1A overexpression via pc-mTL1A in vitro remarkably increased the EMT formation induced by TNF-a. Overall, these findings indicate that the TL1A/DR3 axis may have a therapeutic role for asthmatic with high TNF-a level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Yang, Dong, Zhang, Liu, Pan, Zhang, Xu, Wang, Cui and Dong.)

Background: Helicobacter pylori ( H. pylori ) is a ubiquitous bacterium that affects nearly half of the world's population with a high morbidity and mortality rate. Polymorphisms within the tumor necrosis factor-alpha ( TNF-A ) promoter region are considered a possible genetic basis for this disease., Aim: To functionally characterize the genetic variations in the TNF-A 5'-region (-584 to +107) of Sudanese patients infected with H. pylori using in silico tools., Methods: An observational study was carried out in major public and private hospitals in Khartoum state. A total of 122 gastric biopsies were taken from patients who had been referred for endoscopy. Genomic DNA was extracted. Genotyping of the TNF-A -1030 polymorphism was performed using PCR with confronting two-pair primer to investigate its association with the susceptibility to H. pylori infection in the Sudanese population. Furthermore, Sanger sequencing was applied to detect single nucleotide polymorphisms in the 5'-region (-584 to +107) of TNF-A in H. pylori -infected patients. Bioinformatics analyses were used to predict whether these mutations would alter transcription factor binding sites or composite regulatory elements in this region. A comparative profiling analysis was conducted in 11 species using the ECR browser and multiple-sequence local alignment and visualization search engine to investigate the possible conservation. Also, a multivariate logistic regression model was constructed to estimate odds ratios and their 95% confidence intervals for the association between TNF-A -1030, sociodemographic characteristics and H. pylori infection. Differences were statistically significant if P < 0.05. Statistical analyses were performed using Stata version 11 software., Results: A total of seven single nucleotide polymorphisms were observed in the TNF-A 5'-region of Sudanese patients infected with H. pylori . Only one of them (T > A, -76) was located at the in silico-predicted promoter region (-146 to +10), and it was predicted to alter transcription factor binding sites and composite regulatory elements. A novel mutation (A > T, +27) was detected in the 5' untranslated region, and it could affect the post-transcriptional regulatory pathways. Genotyping of TNF-A -1030 showed a lack of significant association between -1030T and susceptibility to H. pylori and gastric cancer in the studied population ( P = 0.1756) and ( P = 0.8116), respectively. However, a significant association was detected between T/C genotype and H. pylori infection (39.34% vs 19.67%, odds ratio = 2.69, 95% confidence interval: 1.17-6.17, P = 0.020). Mammalian conservation was observed for the (-146 to +10) region in chimpanzee (99.4%), rhesus monkey (95.6%), cow (91.8%), domesticated dog (89.3%), mouse (84.3%), rat (82.4%) and opossum (78%)., Conclusion: Computational analysis was a valuable method for understanding TNF-A gene expression patterns and guiding further in vitro and in vivo experimental validation., Competing Interests: Conflict-of-interest statement: The authors declare that there are no conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: The aim: To improve the effectiveness of treatment of patients with hypertension using metabolic therapy based on the evaluation of endothelial dysfunction indicators, markers of inflammation, and blood lipid spectrum., Patients and Methods: Materials and methods: A clinical study was performed with 72 patients (34 male and 38 female) with stage 2 arterial hypertension of 2-3 degrees, admitted to the cardiology department of the municipal non-profit enterprise "Lviv Emergency Clinical Hospital". The mean age of patients was 44.8±8.5 years. Patients were divided into 2 groups: Group I was taking quercetin in addition to basic therapy (Ramipril/Amlodipine in individually adjusted dose); Group II - had basic therapy following the clinical protocol. The level of nitric oxide, IL-1, IL-6, TNF-a, CRP, seromucoid, blood lipid spectrum was determined., Results: Results: There is a significant decrease in the NO and CRP levels. There is a decrease in the TNF-a level by 31.27±2.13 (p<0.01) after the treatment of patients with hypertension. The TNF-a level decreased by 22.2±1.13 (p<0.01) with the use of basic therapy. IL-1 decreased significantly in the two groups, but it was more pronounced in group I, by 40.68±1.67 (p<0.01) and 21.4±2.1 in group II (p<0.05). There is a positive change in the blood lipid spectrum, but the changes were more pronounced in the group of patients receiving metabolic therapy., Conclusion: Conclusions: The use of quercetin (Corvitin, Quertin) in combination therapy with the combined antihypertensive drug containing ramipril/amlodipine (Egis-Hungary) significantly reduces the levels of nitric oxide, CRP, IL-1, and blood lipid spectrum, which reduces the incidence of complications and progression of hypertension.

Objectives: To study the effect of ultrashort wave combined with loxoprofen sodium on serum inflammatory factors in patients with acute gouty arthritis., Methods: Records of patients with acute gouty arthritis who were treated in The Fourth Hospital of Changsha from May 2018 to September 2020, were reviewed. Of them, 77 cases were selected and divided into two groups based on the received treatment. The control group (n=39) was treated with loxoprofen sodium, and the treatment group (n=38) was treated with an ultrashort wave combined with loxoprofen sodium, for 10 continuous days. The clinical efficacy of the treatment in two groups was analyzed., Results: After treatment, the quality of life of patients in both groups was improved (P < 0.05), but there was no significant difference in the degree of improvement between the two groups (P > 0.05). After treatment, the VAS score of the treatment group was lower than that of the control group (P < 0.05), the improvement of symptoms and signs of the treatment group was better than that of the control group (P < 0.05). Serum CRP and ESR levels in the treatment group were lower than those in the control group (P < 0.05), and the serum IL-1 β, IL-8, TNF-a and MMP-3 levels of the treatment group were lower than those of the control group (P < 0.05). The total effective rate of the treatment group (94.87%) was higher than that of the control group (87.18%), the difference was statistically significant (P < 0.05). No adverse reactions occurred in all patients during the treatment., Conclusion: An ultrashort wave combined with loxoprofen sodium in the treatment of acute gouty arthritis can reduce the inflammatory reaction, improve the degree of joint pain and swelling, improve the curative effect, and do not increase the adverse reactions. The results may be related to the regulation of IL-1 β, IL-8, TNF-a and MMP-3., (Copyright: © Pakistan Journal of Medical Sciences.)

Cerebral palsy (CP) is a group of motor disorders caused by non-progressive lesions of the premature brain with lifelong pathophysiological consequences that include dysregulation of innate immunity. Persistent inflammation with increased levels of circulating pro-inflammatory tumor necrosis factor alpha (TNF-a) is negatively associated with rehabilitation outcome in children with CP. Because of the crosstalk between innate and adaptive immunity, we investigated the effect of CP and rehabilitation exercises on the adaptive immune system in children with CP by measuring the levels of CD3 + , CD4 + , CD8 + Т-cells, and CD22 + B-cells and the levels of immunoglobulins. Children with CP had higher levels of CD3 + , CD4 + , CD8 + Т-cells, and CD22 + B-cells compared to healthy children, and the rehabilitation exercise programs produced better outcomes in terms of increased gains in motor function at an earlier age. Rehabilitation exercises performed over a month resulted in significantly decreased levels of IgA in serum and reduced numbers of B-lymphocytes and reduced IgM levels. Our study suggests that rehabilitation programs with a focus on neuroplasticity and physical exercises in children with CP can reduce both cellular and humoral immune responses., (© 2021 Published by Elsevier Inc.)

Rationale: Depression is a prevalent comorbidity of chronic obstructive pulmonary disease (COPD) that, along with COPD, has been associated with inflammation. An association between inflammation and depression in COPD has not been validated in a large COPD cohort., Methods: Individuals from the University of Pittsburgh SCCOR cohort and the COPDGene cohort with tobacco use history and airway obstruction (FEV 1 /FVC <0.7) were evaluated using the Beck Depression Inventory II (BDI-II) and the Hospital Anxiety and Depression Scale (HADS), respectively. Participants completed symptom-related questionnaires and plasma IL-6 measurements. T -test, Fisher's Exact tests and logistic regression were used for statistical analysis., Results: The SCCOR cohort included 220 obstructed participants: 44% female and 21.4% with elevated depressive symptoms. GOLD staging distribution was predominantly stage I and II. The COPDGene cohort included 745 obstructed participants: 44% female and 13.0% with elevated depressive symptoms. GOLD distribution was predominantly stage II and III. In the SCCOR cohort, correlation between IL-6 and depressive symptoms trended toward significance (p= 0.08). Multivariable modeling adjusted for FEV 1 , age, gender and medical comorbidities showed a significant association (OR = 1.70, 95% CI = 1.08-2.69). IL-6 was significantly associated with elevated depressive symptoms in COPDGene in both univariate (p=0.001) and multivariable modeling (OR = 1.52, 95% CI =1.13-2.04)., Conclusion: Elevated plasma IL-6 levels are associated with depressive symptoms in individuals with COPD independent of airflow limitation and comorbid risk factors for depression. Our results suggest that systemic inflammation may play a significant and possibly bidirectional role in depression associated with COPD., Competing Interests: The authors have no conflicts of interest for this work to disclose., (© 2021 Strollo et al.)

Objective: Chronic periodontitis (CP), aggressive periodontitis (AP), and peri-implantitis (PI) are chronic inflammatory diseases. Tumor necrosis factor-α (TNF-a) is an effective immune inflammatory mediator. Several studies have been conducted to explore the association between the TNF-α (G-308A) polymorphism and susceptibility to CP, AP, and PI. Our objective was to examine whether the TNF-α (G-308A) polymorphism is related to these diseases., Methods: We conducted a meta-analysis to investigate the association between the TNF-α (G-308A) polymorphism and CP, AP, and PI. The PubMed, Embase, CNKI, and Web of Science electronic databases were searched for studies published from inception to August 11, 2020; the reference lists of included studies were also searched. The included studies were assessed in the following genetic models: dominant model, recessive model, allelic model, heterozygous model, and homozygous model., Results: Forty articles (50 comparisons) with 2243 CP, 824 AP, 615 PI, 795 healthy peri-implant, and 3575 healthy controls were considered for the TNF-α (G-308A) polymorphism in this meta-analysis. Variant A of TNF-α (G-308A) was associated with increased AP risk in the general population, especially in Asians, and this polymorphism was significantly associated with elevated risk of CP in Asians and Caucasians. There was no association between the A allele and PI risk. None of the contrasts of the genetic model yielded a significant finding in Latin Americans. Different genotyping methods may affect the association between the TNF-α (G-308A) polymorphism and these diseases., Conclusion: These findings supported that variant A of the TNF-α (G-308A) polymorphism may contribute to CP and AP susceptibility, particularly in Asians and Caucasians. More efforts and further studies with larger sample sizes will be required to validate the risk of CP, AP, and PI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Experimental studies suggest that sodium induced inflammation might be another missing link leading to atherosclerosis. To test the hypothesis that high daily sodium intake induces systemic inflammatory response in humans, we performed a systematic review according to PRISMA guidelines of randomized controlled trials (RCTs) that examined the effect of high versus low sodium dose (HSD vs. LSD), as defined per study, on plasma circulating inflammatory biomarkers. Eight RCTs that examined CRP, TNF-a and IL-6 were found. Meta-analysis testing the change of each biomarker in HSD versus LSD was possible for CRP ( n = 5 studies), TNF-a ( n = 4 studies) and IL-6 ( n = 4 studies). The pooled difference (95% confidence intervals) per biomarker was for: CRP values of 0.1(-0.3, 0.4) mg/L; TNF-a -0.7(-5.0, 3.6) pg/mL; IL-6 -1.1(-3.3 to 1.1) pg/mL. Importantly, there was inconsistency between RCTs regarding major population characteristics and the applied methodology, including a very wide range of LSD (460 to 6740 mg/day) and HSD (2800 to 7452 mg/day). Although our results suggest that the different levels of daily sodium intake are not associated with significant changes in the level of systemic inflammation in humans, this outcome may result from methodological issues. Based on these identified methodological issues we propose that future RCTs should focus on young healthy participants to avoid confounding effects of comorbidities, should have three instead of two arms (very low, "normal" and high) of daily sodium intake with more than 100 participants per arm, whereas an intervention duration of 14 days is adequate.

Background : The objective of this study was to determine the role of single nucleotide polymorphisms (SNPs) in interleukin 1 alpha ( IL-1A ), tumor necrosis factor-alpha ( TNF-A ), and vitamin D receptor ( VDR ) genes on the susceptibility to herniated nucleus pulposus (HNP). Methods : Four databases (PubMed, Embase, Cochrane, and Web of Science) were searched as of April 1 st , 2021. Authors, publication year, targeted genes, genotype and allele frequency in each case and control groups were collected. Newcastle-Ottawa scale was used to evaluate the publication quality. The pooled estimates of association of IL-1A -889C>T (rs1800587), TNF-A -238G>A (rs361525), and VDR TaqI (rs731236) and susceptibility to HNP were assessed using Z test and presented as odd ratio (OR) and 95% confidence intervals (95%CI). Results : We screened 3,067 unique studies for eligibility and three, two and nine studies on IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI were included, respectively, in our meta-analysis. The studies consisting 369 HNP cases and 433 controls for IL-1A -889C>T, 252 cases and 259 controls for TNF-A -238G>A and 1130 cases and 2096 controls for VDR TaqI. Our pooled estimates indicated that there was no significant association of those SNPs with the susceptibility to HNP in any genotype, dominant model, recessive model, or allele comparations. Conclusion : Although individual studies suggested the important role of gene expression dysregulation associated with SNPs in IL-1A , TNF-A , and VDR , our data indicated that IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI had weak association with HNP susceptibility in both genotypes and allele distributions. However, since heterogeneity was identified among studies included in this meta-analysis, further meta-analysis with a larger population and subgroup analysis on specific population are warranted to support this finding., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Azharuddin A et al.)

Background : The pathogenesis of herniated nucleus pulposus (HNP) is complex and may involve the wide variety of gene polymorphism. However, the reports from the existing studies are inconclusive. The objective of this study was to determine the role of single nucleotide polymorphisms (SNPs) in interleukin 1 alpha ( IL-1A ), tumor necrosis factor-alpha ( TNF-A ), and vitamin D receptor ( VDR ) genes on the susceptibility to herniated nucleus pulposus (HNP). Methods : Four databases (PubMed, Embase, Cochrane, and Web of Science) were searched as of April 1 st , 2021. Authors, publication year, targeted genes, genotype and allele frequency in each case and control groups were collected. Newcastle-Ottawa scale was used to evaluate the publication quality. The pooled estimates of association of IL-1A -889C>T (rs1800587), TNF-A -238G>A (rs361525), and VDR TaqI (rs731236) and susceptibility to HNP were assessed using Z test. Results : We screened 3,067 unique studies for eligibility and three, two and nine case-control studies on IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI were included, respectively, in our meta-analysis. The studies consisting 369 HNP cases and 433 controls for IL-1A -889C>T, 252 cases and 259 controls for TNF-A -238G>A and 1130 cases and 2096 controls for VDR TaqI. Our pooled estimates indicated that there was no significant association of those SNPs with the susceptibility to HNP in any genotype, dominant model, recessive model, or allele comparations. Conclusion : Although individual studies suggested the important role of gene expression dysregulation associated with SNPs in IL-1A , TNF-A , and VDR , our data indicated that IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI had weak association with HNP susceptibility in both genotypes and allele distributions. However, since heterogeneity was identified among studies included in this meta-analysis, further meta-analysis with a larger population and subgroup analysis on specific population are warranted to support this finding., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Azharuddin A et al.)

Background : The pathogenesis of herniated nucleus pulposus (HNP) is complex and may involve the wide variety of gene polymorphism. However, the reports from the existing studies are inconclusive. The objective of this study was to determine the role of single nucleotide polymorphisms (SNPs) in interleukin 1 alpha ( IL-1A ), tumor necrosis factor-alpha ( TNF-A ), and vitamin D receptor ( VDR ) genes on the susceptibility to herniated nucleus pulposus (HNP). Methods : Four databases (PubMed, Embase, Cochrane, and Web of Science) were searched as of April 1 st , 2021. Authors, publication year, targeted genes, genotype and allele frequency in each case and control groups were collected. Newcastle-Ottawa scale was used to evaluate the publication quality. The pooled estimates of association of IL-1A -889C>T (rs1800587), TNF-A -238G>A (rs361525), and VDR TaqI (rs731236) and susceptibility to HNP were assessed using Z test. Results : We screened 3,067 unique studies for eligibility and three, two and nine case-control studies on IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI were included, respectively, in our meta-analysis. The studies consisting 369 HNP cases and 433 controls for IL-1A -889C>T, 252 cases and 259 controls for TNF-A -238G>A and 1130 cases and 2096 controls for VDR TaqI. Our pooled estimates indicated that there was no significant association of those SNPs with the susceptibility to HNP in any genotype, dominant model, recessive model, or allele comparations. Conclusion : Although individual studies suggested the important role of gene expression dysregulation associated with SNPs in IL-1A , TNF-A , and VDR , our data indicated that IL-1A -889C>T, TNF-A -238G>A, and VDR TaqI had weak association with HNP susceptibility in both genotypes and allele distributions. However, since heterogeneity was identified among studies included in this meta-analysis, further meta-analysis with a larger population and subgroup analysis on specific population are warranted to support this finding., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Azharuddin A et al.)

Background: Bacteria infection and laryngopharyngeal reflux (LPR) were believed the important pathogenesis of chronic otitis media with effusion (COME). But no study researched the relationship between them on COME., Aims: To confirm bacterial could arrive middle ear through LPR and produced acid metabolites to activate the pepsinogen of LPR causing COME., Material and Methods: Children (65) diagnosed COME with 122 middle ear effusions were included in COME group. Children (22) with congenital/acquired profound deafness with 22 middle ear lavage were included in CI group. Pepsin A concentration in the effusion and lavage fluid were measured. The DNA of the bacteria, IL-8 and TNF-α in the effusion were detected., Results: The average concentration of pepsin A in the effusions and lavage were 176.65 ± 242.09 and 19 ng/ml. Bacterial infection rates were 75.76% and 24.24% in the pepsin A(+) and pepsin A(-) patients. In the bacterial (+), the patients of pepsin A(+) was 4.33 times higher than those of pepsin A(-). TNF-α in pepsin A(+) was higher than that in pepsin A(-). TNF-α and IL-8 were higher in bacteria(+) than those of bacteria(-)., Conclusions: Bacterial infection and LPR might act in synergy in the pathogenesis of COME., Significance: First time to propose LPR and bacterial infection might work synergistically to cause COME.

Purpose: To investigate aqueous cytokine levels in association with hemorrhage in proliferative diabetic retinopathy (PDR) in patients with type 2 diabetes mellitus., Methods: Sixty-six eyes with treatment-naïve PDR, including 26 hemorrhagic and 40 nonhemorrhagic eyes were included in this institutional study. Aqueous humor levels of interleukin (IL)-1b, IL-6, IL-8, IL-10, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and soluble VEGF receptor-1 were obtained by multiplex bead assay. Visual acuity and hemorrhage area measurements were obtained, and correlations between cytokine levels and hemorrhage were identified., Results: Levels of MCP-1, TNF-α, and VEGF were higher in hemorrhagic eyes (1506.77 vs. 2131.31 pg/mL, 0.43 vs. 0.63 pg/mL, and 103.96 vs. 206.96 pg/mL; P = 0.050, 0.022, and 0.027, respectively). The levels of IL-8, MCP-1, TNF-α, and VEGF showed positive correlation with visual acuity (P = 0.019, 0.015, 0.001, and 0.014, respectively). The hemorrhage area revealed positive correlation with TNF-α and VEGF levels (P = 0.001 and < 0.001, respectively)., Conclusion: The presence and amount of hemorrhage in PDR were associated not only with VEGF concentration, but also with the levels of certain inflammatory cytokines, suggesting a role of both VEGF and inflammation in hemorrhagic eyes.

Pro-inflammatory cytokines play critical roles in regulating valvular interstitial cell (VIC) phenotypic changes that can cause heart valve fibrosis and calcification. Tumor necrosis factor alpha (TNF-α) is a cytokine known to influence VIC behavior and has been reported at high levels in calcified valves ex vivo. We sought to understand the specific effects of TNF-α on VIC phenotypes (eg, fibroblast, profibrotic activated myofibroblasts) and its link with heart valve disorders. We characterize human aortic valve tissue from patients with valve disorders and identify a high variability of fibrotic and calcific markers between tissues. These results motivated in vitro studies to explore the effects of TNF-α on defined VIC fibroblasts and profibrotic activated myofibroblasts, induced via FGF-2 and TGF-β1 treatment. Using 3D hydrogels to culture VICs, we measure the effect of TNF-α (0.1-10 ng/mL) on key markers of fibrosis (eg, αSMA, COL1A1) and calcification (eg, RUNX2, BMP2, and calcium deposits). We observe calcification in TNF-α-treated VIC activated myofibroblasts and identify the MAPK/ERK signaling cascade as a potential pathway for TNF-α mediated calcification. Conversely, VIC fibroblasts respond to TNF-α with decreased calcification. Treatment of VIC profibrotic activated myofibroblast populations with TNF-α leads to increased calcification. Our in vitro findings correlate with findings in diseased human valves and highlight the importance of understanding the effect of cytokines and signaling pathways on specific VIC phenotypes. Finally, we reveal MAPK/ERK as a potential pathway involved in VIC-mediated matrix calcification with TNF-α treatment, suggesting this pathway as a potential pharmaceutical target for aortic valve disease., (© 2021 Federation of American Societies for Experimental Biology.)

Sepsis is a systemic inflammatory disorder induced by a dysregulated immune response to infection resulting in dysfunction of multiple critical organs, including the intestines. Previous studies have reported contrasting results regarding the abilities of exosomes circulating in the blood of sepsis mice and patients to either promote or suppress inflammation. Little is known about how the gut epithelial cell-derived exosomes released in the intestinal luminal space during sepsis affect mucosal inflammation. To study this question, we isolated extracellular vesicles (EVs) from intestinal lavage of septic mice. The EVs expressed typical exosomal (CD63 and CD9) and epithelial (EpCAM) markers, which were further increased by sepsis. Moreover, septic-EV injection into inflamed gut induced a significant reduction in the messaging of pro-inflammatory cytokines TNF-a and IL-17A. MicroRNA (miRNA) profiling and reverse transcription and quantitative polymerase chain reaction (RT-qPCR) revealed a sepsis-induced exosomal increase in multiple miRNAs, which putatively target TNF-a and IL-17A . These results imply that intestinal epithelial cell (IEC)-derived luminal EVs carry miRNAs that mitigate pro-inflammatory responses. Taken together, our study proposes a novel mechanism by which IEC EVs released during sepsis transfer regulatory miRNAs to cells, possibly contributing to the amelioration of gut inflammation.

Fungal endophthalmitis is a serious and vision-threatening infection which requires an immediate and effective treatment approach. Our research aims to elucidate the histological effects of the intravitreal injection of the maximum safe dosage of voriconazole and micafungin on retina. Six albino New Zealand White Rabbits were used. In experimental animals, a solution of voriconazole (Group V) or micafungin (Group M) was intravitreally injected in the right eye, while in control animals, balanced salt solution was intravitreally injected in the left eye (Group C). Euthanasia was performed ten days post injection and the retina was removed and prepared for histological examination with a light and electron microscope. Eosin-hematoxylin staining did not reveal any pathological changes in any of the samples examined. The immunohistochemical staining for Tumor Necrosis Factor alpha (TNF-a) marker was detected as negative in all samples, while Interleukin 6 (IL-6) marker was detected as mild only in the group injected with voriconazole. Electron microscopy revealed several ultrastructural alterations in retinal layers in both groups of experimental animals. Histological retinal lesions, revealed with electron microscopy in the present investigation, raises the question of the safe usage of these antifungal agents in the treatment of fungal intraocular infections in the future.

To study the mechanisms by which the p.R47H variant of the microglia gene and Alzheimer's disease (AD) risk factor TREM2 increases dementia risk, we created Trem2 R47H KI rats. Trem2 R47H rats were engineered to produce human Aβ to define human-Aβ-dependent and -independent pathogenic mechanisms triggered by this variant. Interestingly, pre- and peri-adolescent Trem2 R47H rats present increased brain concentrations of TNF-α, augmented glutamatergic transmission, suppression of Long-term-Potentiation (LTP), an electrophysiological surrogate of learning and memory, but normal Aβ levels. Acute reduction of TNF-α activity with a neutralizing anti-TNF-α antibody occludes the boost in amplitude of glutamatergic transmission and LTP suppression observed in young Trem2 R47H/R47H rats. Thus, the microglia-specific pathogenic Trem2 variant boosts glutamatergic neuronal transmission and suppresses LTP by increasing brain TNF-α concentrations, directly linking microglia to neuronal dysfunction. Future studies will determine whether this phenomenon represents an early, Aβ-independent pathway that facilitates dementia pathogenesis in humans., Competing Interests: SR, WY, MT, TY, KN, LD No competing interests declared, (© 2020, Ren et al.)

Background: Patients with liver cirrhosis may develop hepatic encephalopathy. Rats with chronic hyperammonemia exhibit neurological alterations mediated by peripheral inflammation and neuroinflammation. Motor incoordination is due to increased TNF-a levels and activation of its receptor TNFR1 in the cerebellum. The aims were to assess (a) whether peripheral inflammation is responsible for TNF-a induction in hyperammonemic rats, (b) the cell type(s) in which TNF-a is increased, (c) whether this increase is associated with increased nuclear NF-κB and TNFR1 activation, (d) the time course of TNF-a induction, and (e) if TNF-a is induced in the Purkinje neurons of patients who die with liver cirrhosis., Methods: We analyzed the level of TNF-a mRNA and NF-κB in microglia, astrocytes, and Purkinje neurons in the cerebellum after 1, 2, and 4 weeks of hyperammonemia. We assessed whether preventing peripheral inflammation by administering an anti-TNF-a antibody prevents TNF-a induction. We tested whether TNF-a induction is reversed by R7050, which inhibits the TNFR1-NF-κB pathway, in ex vivo cerebellar slices., Results: Hyperammonemia induced microglial and astrocyte activation at 1 week. This was followed by TNF-a induction in both glial cell types at 2 weeks and in Purkinje neurons at 4 weeks. The level of TNF-a mRNA increased in parallel with the TNF-a protein level, indicating that TNF-a was synthesized in Purkinje cells. This increase was associated with increased NF-κB nuclear translocation. The nuclear translocation of NF-κB and the increase in TNF-a were reversed by R7050, indicating that they were mediated by the activation of TNFR1. Preventing peripheral inflammation with an anti-TNF-a antibody prevents TNF-a induction., Conclusion: Sustained (4 weeks) but not short-term hyperammonemia induces TNF-a in Purkinje neurons in rats. This is mediated by peripheral inflammation. TNF-a is also increased in the Purkinje neurons of patients who die with liver cirrhosis. The results suggest that hyperammonemia induces TNF-a in glial cells and that TNF-a released by glial cells activates TNFR1 in Purkinje neurons, leading to NF-κB nuclear translocation and the induction of TNF-a expression, which may contribute to the neurological alterations observed in hyperammonemia and hepatic encephalopathy.

Group 2 innate lymphoid cells (ILC2s) can initiate pathologic inflammation in allergic asthma by secreting copious amounts of type 2 cytokines, promoting lung eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. We discovered that the TNF/TNFR2 axis is a central immune checkpoint in murine and human ILC2s. ILC2s selectively express TNFR2, and blocking the TNF/TNFR2 axis inhibits survival and cytokine production and reduces ILC2-dependent AHR. The mechanism of action of TNFR2 in ILC2s is through the non-canonical NF-κB pathway as an NF-κB-inducing kinase (NIK) inhibitor blocks the costimulatory effect of TNF-α. Similarly, human ILC2s selectively express TNFR2, and using hILC2s, we show that TNFR2 engagement promotes AHR through a NIK-dependent pathway in alymphoid murine recipients. These findings highlight the role of the TNF/TNFR2 axis in pulmonary ILC2s, suggesting that targeting TNFR2 or relevant signaling is a different strategy for treating patients with ILC2-dependent asthma., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Probiotic use to prevent gastrointestinal infections in critical care has shown great promise in recent clinical trials. Although well-documented benefits of probiotic use in intestinal disorders, the potential for probiotic treatment to ameliorate liver injury and hypoxic hepatitis following sepsis has not been well explored., Methods: In order to evaluate, if Lactobacillus rhamnosus GG (LGG) treatment in septic rats will protect against liver injury, this study used 20-22-week-old Sprague-Dawley rats which were subjected to cecal ligation and puncture to establish sepsis model and examine mRNA and protein levels of IL-1β, NLRP3, IL-6, TNF-a, VEGF, MCP1, NF-kB and HIF-1α in the liver via real-time PCR, Elisa and Western blot., Results: This study showed that LGG treatment significantly ameliorated liver injury following experimental infection and sepsis. Liver mRNA and protein levels of IL-1β, NLRP3, IL-6, TNF-a, VEGF, MCP1, NF-kB and HIF-1α were significantly reduced in rats receiving LGG., Conclusions: Thus, our study demonstrated that LGG treatment can reduce liver injury following experimental infection and sepsis and is associated with improved hypoxic hepatitis. Probiotic therapy may be a promising intervention to ameliorate clinical liver injury and hypoxic hepatitis following systemic infection and sepsis.